What is Natural Products?

Natural products are organic molecules isolated from animals, plants, or microbes that can be used to treat human disease.

Overview

Through evolutionary pressure, nature has guided the production of an immense diversity of organic molecules for a variety of biological purposes. In order to search natural sources for new therapeutics, generally crude fractions of biological material (often plants, marine life, or soil microbes that cannot be cultured) are screened for biological activity. Fractions with activity are further purified and retested until the bioactive natural product is identified.

Natural products are the cornerstone of modern therapeutics. Building on the discovery of morphine from poppy seeds in the 1800s and penicillin from mold in the 1920s, natural products have been a key source of new therapeutics. Natural products are currently used to treat cancer, high levels of cholesterol, fungal infections, bacterial infections, and parasitic diseases. As of 1990, nearly 80% of all drugs in use were natural products or natural product derivatives.1

Despite the success of natural products as therapeutics, drug discovery for natural products faces many challenges:2

  • Working with biological materials, many of which must be collected rather than laboratory raised, is inherently variable. The level of an active product in an organism may vary with that organism’s life cycle or environmental conditions, which can lead to variability in materials.
  • Crude fractionations of biological materials are not as amenable to high throughput screening as highly pure fully synthetic chemical libraries.
  • Crude fractions used for screening are generally mixtures of hundreds of components, which can be quite challenging to fully purify and identify.
  • Natural products, once identified, are often complex molecules that are challenging and/or expensive to produce synthetically.

The number of natural product drug discovery programs has steadily declined since the 1980s, primarily because pharmaceutical companies have shifted to using synthetic chemical libraries that are more amenable to high throughput screening and simplified synthesis. Between 1981 and 2002, approximately 50% of all new chemical entities approved by the U.S. Food & Drug Administration (FDA) were natural products, natural product derivatives, or synthetic mimetics related to natural products.2,3 However, clinical trials for new natural product therapeutics dropped 30% between 2001 and 2008.1

Despite this shift, natural products remain an important part of the drug discovery process. They are often used as a starting point for the production of simplified bioactive molecules or to inform the production of synthetic small molecule libraries that are more amenable to high throughput screening. Automated fractionation and characterization methods to improve screening, molecular modeling programs to guide rational modification of natural products, and engineering strategies for heterologous production of natural products in laboratory amenable organisms are making natural product drug discovery and development more accessible and may lead to more programs in this area.

Existing Products

There are numerous natural products that are approved for the treatment of a variety of diseases. Examples of approved natural product therapeutics are listed in the table below.

Product Disease Notes
Lovastatin Atherosclerosis/heart disease First isolated from the mushroom Aspergillus terreus in 1982
Paclitaxel Cancer First isolated from the bark of the Pacific yew tree, Taxus brevifolia, in 1967
Ivermectin (derivative of natural product avermectin) Parasitic helminth infections: Lymphatic filariasis and Onchocerciasis Avermectin was first isolated in 1978 from the soil actinomycete Streptomyces avermitilis
Artemisinin Malaria First described for treatment of fever in traditional Chinese medicine. First isolated from the leaves of the plant Artemisia annua in 1972.
Streptomycin Antibiotic First isolated from the actinobacterium Streptomyces griseus in 1943.

Natural Products as Non-Neglected Tropical Disease Therapeutics

Natural products and their derivatives have been used to treat a variety of non-neglected tropical diseases, including:

  • Cancer
  • Atherosclerosis/heart disease
  • Autoimmune diseases
  • Chronic pain

As natural products span a wide diversity of chemical scaffolds, mechanisms of actions, and molecular targets, it is difficult to draw generalizations across this class. However, the diversity of diseases that have benefitted from natural product therapeutics is a testament to this strategy for novel therapeutic discovery.

Natural Products as Neglected Tropical Disease Therapeutics

Natural products are used to treat a variety of neglected tropical diseases. Specific neglected tropical diseases with natural product therapeutics include:

  • Tuberculosis
  • Lymphatic filariasis
  • Malaria

Streptomycin, an antibiotic derived from the actinomycete Streptomyces griseus, was the first antibiotic successfully used to treat tuberculosis. The discovery of streptomycin in 1943, followed by its first successful use for the treatment of tuberculosis in 1944, led to the presentation of the 1952 Nobel Prize in Physiology or Medicine to Selman Waksman, the American scientist who made the discovery.4 Although drug resistance ultimately limited the usefulness of streptomycin as a monotherapy, it is still used as part of multidrug combination therapy for the treatment of tuberculosis with meningitis complications.

Ivermectin is a derivative of the natural product avermectin, a compound that was also isolated from an antinomycete of the genusStreptomyces. It is used to treat a variety of infections caused by parasitic worms known as helminths, including strongyloides, onchocerciasis, and lymphatic filariasis. Ivermectin has partial efficacy on other human helminth infections and is also used to treat external infestations of scabies and lice. In animals, it is widely used for the treatment and prevention of heartworm.

One of the most interesting stories of natural product drug discovery for neglected diseases is that of artemisinin for the treatment of malaria. Artemisinin is a naturally occurring chemical compound found in the leaves of the plant Artemisia annua. Records of the use of this plant for the treatment of malaria date back nearly 2000 years, but the artemisinin compound was not extracted from the plant and characterized until the 1970s. Development of artemisinin as a drug faced several challenges. Extraction of the compound from plants was expensive, making the drug largely unaffordable to those in need. Chemical synthesis of the compound was achieved but proved difficult and costly without much benefit over extraction. As an alternative, genetic engineering of yeast was used to create a yeast strain that could produce the artemisinin synthetic intermediate, artemisinic acid.5 This method of production drastically reduced the cost of artemisinin production. Artemisinin is now widely available as part of artemisinin combination therapies (ACTs). Multiple semi-synthetic and synthetic derivatives are also now in use or in development for the treatment of malaria.

References

  1.  Li JWH and Vederas JC (2009) “Drug discovery and natural products: end of an era or an endless frontier?” Science 325: 161-165.
  2. Koehn FE and Carter GT (2005) “The evolving role of natural products in drug discovery.” Nature Reviews Drug Discovery 4: 206-220.
  3. Chin YW (2006) “Drug Discovery from Natural Sources.” The AAPS Journal 8: E239-E253.
  4. NobelPrize.org article “Tuberculosis,” available here.
  5. Ro DK et al. (2006) “Production of the antimalarial drug precursor artemisinic acid in engineered yeast.” Nature 440: 940-943.

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Pipline

Analysis

Natural products are in use or in development for a variety of diseases. New natural products are in development for the treatment of leishmaniasis, tuberculosis, and dengue fever. The pipeline above excludes artemisinin derivatives in development for malaria, but more information on these products can be found under the malaria disease profile.

The relative strengths, weaknesses, opportunities, and risk for natural products that are currently in use or in development for neglected tropical diseases are summarized here.

  Strengths Weaknesses Opportunities Risks
Natural products
Relevant neglected tropical diseases: 

Malaria (multiple artemisinin-related products on market and in late stage development)

Tuberculosis (streptomycin on market; multiple products in discovery stage of development)

Dengue fever (ASB010 and PYN-18, pre-clinical)

Leishmaniasis (Licochalcone A, pre-clinical)
With the exception of malaria, new natural product programs are primarily focused on novel or unknown mechanisms of action relative to approved products for these diseases which will reduce the chance for resistance Natural product drug discovery can be labor intensive and expensive

Mechanism of action of natural products screened against whole cells rather than specific targets can be difficult to identify (e.g., mechanism of action of artemisinin in malaria is still not fully understood)
Additional screening of natural products against all neglected tropical diseases

Generation of synthetic chemical libraries based on hits from discovery stage natural product programs
Majority of programs are very early stage, so potential for successful application in humans is not known

Identified natural products may be complex and difficult to produce at low cost for use in resource poor settings

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To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

Database Resources

There are numerous databases of natural product compound information including:

Assays

Assays and associated technologies to separate and analyze natural products are advancing. Representative examples include:1,2

  • Automated fractionation, plating, and analysis of crude extracts to facilitate high throughput screening and bioactive compound identification
  • Concurrent screening of fractions using positive and negative selection (primarily to reduce false positives from natural products that are already known)
  • Advances in mass spectrometry and NMR analysis methods to identify bioactive compounds

For the most part, screening of natural products or fractionated biological materials to discover new natural product therapeutics is primarily limited by the availability of screening assays for the disease of interest. More information on the availability of assays for screening can be found under the tools section for each specific neglected tropical disease.

References

  1. Li JWH and Vederas JC (2009) “Drug discovery and natural products: end of an era or an endless frontier?” Science 325: 161-165.
  2. Koehn FE and Carter GT (2005) “The evolving role of natural products in drug discovery.” Nature Reviews Drug Discovery 4: 206-220.

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.